1. Technical Field
The present invention relates to glycyrrhizinates of morphinan derivatives and pharmaceutical use thereof.
2. Description of Related Art
Dextromethorphan and dimemorfan are non-opioid antitussive drugs, safely used in the clinic. 3-Methoxy-morphinan is a dextromethorphan's metabolite. 3-methoxy-morphinan has a spinal anaesthetic effect. 3-methyl-morphinan is a dimemorfan's metabolite. Codeine is an effective narcotic antitussive agent. Buprenorphine is a semi-synthetic narcotic agonist-antagonist analgesic. Butorphanol is a morphinan-type synthetic opioid analgesic. Nalbuphine is a semi-synthetic narcotic agonist-antagonist analgesic. Naloxone is a drug used to counter the effects of opioid overdose. Nalmefene is an opioid receptor antagonist used primarily in the management of alcohol dependence. Naltrexone is an opioid receptor antagonist used primarily in the management of alcohol dependence and opioid dependence. Oxymorphone is a powerful semi-synthetic opioid analgesic.
Dextromethorphan was used as a method of treating chronic pain under U.S. Pat. No. 2,676,177 and for inhibiting the development of tolerance to and/or dependence on a narcotic analgesic under U.S. Pat. No. 5,321,012. The U.S. FDA approved dextromethorphan for over-the-counter sale as a cough suppressant in 1958. The dimemorfan phosphate was discovered through extensive screening of morphinan derivatives and was introduced as an antitussive agent in Japan in 1975. Codeine was used as an opiate for its analgesic, antitussive, and antidiarrheal properties.
Buprenorphine, butorphanol, nalbuphine and oxymorphone are opioids that were indicated for the relief of moderate to severe pain.
Naloxone was used to counter the effects of opioid overdose. Nalmefene was used primarily in the management of alcohol dependence. Naltrexone was used primarily in the management of alcohol dependence and opioid dependence.
Glycyrrhizinic acid has various pharmacological effects. Glycyrrhizinic acid is an ancillary drug used clinically in China for protection of liver function and treatment of tumors (Chem Biol Interact. 2009 Sep. 14; 181(1):15-9. Epub 2009 May 6). Glycyrrhizinic acid has been used as a treatment for chronic hepatitis. Glycyrrhizinic acid reduced the infiltration of inflammatory cells and liver injury (J Pharm Pharmacol. 2008 January; 60(1):91-7). Glycyrrhizinic acid could be beneficial against liver diseases where oxidative stress is known to play a crucial role (Food Chem Toxicol. 2009 February; 47(2):339-47). Glycyrrhizinic acids also have been used for numerous other medical purposes, particularly as an expectorant and a treatment of peptic ulcers. Glycyrrhizinic acid might also be an effective drug against severe acute respiratory syndrome (Int Immunopharmacol. 2005 March; 5(3):571-80).
Glycyrrhizinic acid has anti-inflammatory activity and has been used for the treatment of chronic viral hepatitis. In Japan, glycyrrhizinic acid injections have been used as a therapeutic drug for allergy inflammation since 1948 and for chronic hepatitis since 1979 (Yakugaku Zasshi. 2007 July; 127(7):1103-14). Glycyrrhizinic acid has been used for the treatment of chronic liver diseases in Japan, and a distinct improvement of liver function tests has been reported (Jpn J. Pharmacol. 1992 March; 58(3):209-18).
Discomfort due to bitter taste is a common complaint from patients, particularly are children and older men, administered some drugs. Dextromethorphan, dimemorfan, codeine, buprenorphine, butorphanol, nalbuphine, naloxone, nalmefene, naltrexone and oxymorphone are morphinan derivatives. Though they very often are used to treat some diseases, but they taste bitter.
Dextromethorphan hydrobromide is a practically odorless, white to almost white crystalline powder with a bitter taste. Dimemorfan phosphate is a white to yellowish-white, odorless, bitter crystals. Codeine base is an odorless crystals or a crystalline powder with a bitter taste.
Opioids usually have a very bitter taste. Buprenorphine is unflavored and has a bitter, medicinal taste (J Subst Abuse Treat. 2010 January; 38(1):83-9). Butorphanol tartrate is a white, crystalline powder that is sparingly soluble in water and insoluble in alcohol. It has a bitter taste. Nalbuphine hydrochloride is an opiate analgesic. It has a bitter taste to patients. Sublingual naloxone has a bitter taste (Drug Alcohol Depend 25:27-34, 1990). Naltrexone hydrochloride occurs as white crystals having a bitter taste.
Due to dextromethorphan is water insoluble, and dextromethorphan must be utilized in the form of a salt, typically the hydrobromide monohydrate salt (dextromethorphan hydrobromide). Dextromethorphan hydrobromide is readily absorbed in the patient's body, but its action is relatively short-lived. The patient is required to take relatively high doses several times a day. It would be very desirable if a form of dextromethorphan that would has more extended-release property is available. Therefore, the dextromethorphan would be slowly released into the patient's bloodstream over a prolonged period of time.
At recommended doses, dextromethorphan hydrobromide produces little or no CNS depression. At higher doses (recreational doses), positive effects may include acute euphoria, elevated mood, dissociation of mind from body, creative dream-like experiences, and increased perceptual awareness. Other effects include disorientation, confusion, pupillary dilation, and altered time perception, visual and auditory hallucinations, and decreased sexual functioning. Abused doses are capable of impairing judgment, memory, language, and other mental performances.
Large doses of bromide cause nausea and vomiting, abdominal pain, coma and paralysis. The chronic state of bromide intoxication is reported as bromism. The signs and symptoms are referable to the nervous system, skin, glandular secretions and gastrointestinal tract (Crit Rev Toxicol. 1987; 18(3):189-213).
Glycyrrhizic (Glycyrrhizinic) acid has relatively mild acute toxicity and glycyrrhizic (glycyrrhizinic) acid is also emphasized by the “generally recognized as safe” (GRAS) status in the USA in 1983 (Hum Exp Toxicol. 2000 August; 19(8):434-9).